Method for identifying at risk cardiovascular disease patients

ABSTRACT

The invention provides a method for identifying patients with normal NCEP lipid levels who are in need of treatment for cardiovascular disease comprising measuring one or more LDL or HDL particle subclass levels and identifying abnormal LDL or HDL subclass levels. LDL III a+b and HDL 2b are preferred subclasses.

FIELD OF THE INVENTION

This invention is in the field of cardiovascular healthcare managementand patient treatment.

BACKGROUND OF THE INVENTION

According to the National Cholesterol Education Program (NCEP)guidelines, low density lipoprotein (LDL) cholesterol goals and criteriafor Therapeutic Lifestyle Changes and Drug Therapy in different riskcategories are as follows: LDL level to ini- LDL level to Risk tiateTherapeutic consider Drug Category LDL Goal Lifestyle Changes TherapyCHD or CHD <100 mg/dL 100 mg/dL 130 mg/dL Risk (10 yr risk 10-20%)Equivalents 160 mg/dL (10-yr risk <10%) 2+ Risk <130 mg/dL 130 mg/dL 130mg/dL Factors (10 yr risk 10-20%) 160 mg/dL (10-yrrisk <10%) 0-1 Risk<160 mg/dL 160 mg/dL 190 mg/dL Factor

The invention utilizes the health care management system described in WO01/41037A3 to study data from patient populations for cardiovascularrisk factors especially those factors related to LDL and HDL subclass.WO 01/41037AC is incorporated herein in its entirety. The text, HeartDisease Breakthrough, by Thomas Yannios, M.D. John Wiley & Son, Inc.,New York, 1999 discusses management of heart disease and the role of HDLand LDL subclasses and is incorporated herein by reference.

SUMMARY OF THE INVENTION

In analyzing LDL and HDL subclass data from more than 65,000cardiovascular patients, it has been found that indicia for patienttreatment can be derived from LDL and HDL subclass information that isnot available from NCEP risk factor data. Thus, the invention permitsthe identification of patients with healthy low density lipoproteinconcentration (LDLC) and high density lipoprotein concentration (HDLC)levels who have an undesirable small dense LDL trait and deficientreverse cholesterol transport system. For example, it has unexpectedlybeen found that the determination of LDL III a+b permits theidentification of patients who are in need of therapeutic lifestylechanges and drug therapy which are not evident from NCEP guidelinesbased on a conventional panel of lipid assays. Similarly HDL 2b valuescan be used to identify patients in need of lifestyle change or drugtherapy. LDL III a+b and HDL 2b values combined is a powerful tool foridentifying patients who need treatment which NCEP data indicate are notin need of treatment.

More particularly, it has been determined that cardiovascular patientswith LDL III a+b levels, small dense LDL particles, of about 15% or moreare in need of more aggressive cardiovascular healthcare management,i.e., lifestyle changes and drug therapy. This LDL III a+b measurementidentifies about 40% of patients in need of treatment that are missed byonly using NCEP guidelines. Thus, the NCEP guidelines for treatmentwhich are based on the basic lipid panel described above are not capableof determining cardiovascular risk in a significant subpopulation ofpatients and result in not treating at risk cardiovascular patients.

The invention therefore encompasses a method for identifying patientswith normal NCEP lipid levels who are in need of treatment forcardiovascular disease comprising measuring one or more LDL or HDLparticle subtraction levels and identifying abnormal LDL or HDLsubtraction levels.

LDL III a+b are the preferred LDL subclasses to be measured and HDL 2bis the preferred HDL subclass. Other factors such as lipoprotein (a)(Lp(a)), triglycerides, and homocysteine also provide highly usefulinformation. LDL and HDL subclasses are determined by gradient gelelectrophoresis (GGE), NMR, ultracentrifugation, or ion mobilityanalysis.

DETAILED DESCRIPTION OF THE INVENTION

Database Statistics:

There are 65,536 patients in the database of which 51% (33,463) haveLDLC<130 mg/dL and 44% (20,149) have levels of LDLC<100 mg/dL.Furthermore, 47% (31,102) of all patients in the database have LDLIIIa+b measurements.

Methods:

Database search criteria was set at two LDL levels: patients withLDLC<130 and patients with LDLC<100.

Results:

Of the patients with LDLC<130 and measured LDL—by gradient gelelectrophoresis (GGE), 74% had an LDL IIIa+b 15% (see below)—a valuedocumented to raise cardiovascular risk by 3-fold.

A. LDLC<130 mg/dL=33,463 patients (51% of total volume)

-   -   1. LDLC<130 mg/dL with LDLIIIa+b 15%=74%    -   2. LDLC<130 mg/dL with LDLIIIa+b 20%=55%    -   3. Pheno A=19,653 or 44%    -   4. Pheno AB=5,568 or 17%    -   5. Pheno B=13,173 or 39%    -   **Note: Each database has a limiting population factor. The        above search only uses two variables and the limiting factor is        LDLIIIa+b (n=18,797). Each introduction of a new variable limits        the population of the result.

Of the patients with LDLC<100 and measured LDL-GGE, 85% of them had aLDL IIIa+b 15%(see below).

B. LDLC<100 mg/dL=20,149 patients (44% of total volume)

-   -   1. LDLC<100 mg/dL with LDLHIa+b 15%=85%    -   2. LDLC<100 mg/dL with LDLHIa+b 20%=70%    -   3. Pheno A=8,411 or 42%    -   4. Pheno AB=3,431 or 17%    -   5. Pheno B=8,307 or 41%

In either case, patients considered to be under “control” and thoughtnot to require further treatment by NCEP guidelines had a preponderanceof small, dense atherogenic particles and required varying degrees ofaggressive treatment.

Another aspect of the invention involves utilizing the HDL 2b subclassdata in the database. If the LDLC<100 database is used, the inventionprovides a test for hard to treat or difficult patients. But, theLDL<100 database also illustrates that just driving down LDLC is notalways the solution. On the other hand, the LDL<130 database may seemtoo conservative because the NCEP goal is 100 for patients with CHD orCHD risk equivalents, but it does adhere to the population of patientswho have family history or haven't been treated and need to establish abaseline to monitor therapy. The four variable search of patients withLDLC<130, HDL>40, an LDL IIIa+b value, and/or an HDL 2b value exhibitssimilar results from the LDLC<130 database.

C. LDLC<130 mg/dL+HDLC>40 mg/dL=13,810

-   -   1. (C) with LDLIIIa+b 15%=70%    -   2. (C) with LDLIIIa+b 20%=43%    -   3. (C) with HDL 2b>20%=56%    -   4. (C) with LDLIIIa+b 15%+HDL 2b>20%=59%    -   5. (C) with LDLIIIa+b 20%+HDL 2b>20%=40%

If it is assumed these patients have 2+risk factors, the LDLC<130 andHDL>40 are at “healthy” levels according to NCEP, but the same verdictis displayed as the above database search. 70% of the population has anelevated LDL IIIa+b. When HDL 2b is added to the equation, thepercentage of patients with both abnormal LDL IIIa+b and HDL 2b valuesslightly lessen to 59%. Thus, about 6 out of 10 patients with “healthy”LDLC and HDLC levels express both the small dense LDL trait anddeficient reverse cholesterol transport system.

The other four variable search of patients with LDLC<100, HDL>40, an LDLIIIa+b value, and/or an HDL 2b value exhibits similar results from itsdatabase sibling. The concomitant risk factors of elevated LDLIIIa+b anddeficient HDL 2b occur 91% of the time.

D. LDLC<100 mg/dL+HDLC>40 mg/dL=11,334

-   -   1. (D) with LDLIIIa+b 15%=84%    -   2. (D) with LDLIIIa+b 20%=60%    -   3. (D) with HDL 2b>20%=53%    -   4. (D) with LDLIIIa+b 15%+HDL 2b>20%=91%    -   5. (D) with LDLIIIa+b 20%+HDL 2b>20%=68%

Physicians who have patients with an LDLC value under control (<100)often conclude that they need no further information for treating thepatient. This is not the case (See B), 85% of the population with LDLIIIa+b values were elevated and were in need of treatment.

There are several other aspects of the invention derived from thedatabase analysis such as 61% of patients with LDL<100 or LDL<130 andTG<150 still have deficient or abnormal HDL 2b values (LDLC undercontrol and triglyceride metabolism working fine, but unapparentdeficient reverse cholesterol transport). All of these newly discoveredrelationships are summarized below in their respective database(LDLC<130 or LDLC<100).

Database Informatics (LDL<130 mg/dL)

-   (Total Database Volume: 65,536)-   (Total of patients with LDL IIIa+b values: 31,102 (47%))    A. LDLC<130 mg/dL=33,463 patients (73% of total volume    -   1. LDLC<130 mg/dL with LDLHIa+b 15%=74%    -   2. LDLC<130 mg/dL with LDLIIIa+b 20%=55%        -   a. Pheno A=19,653 or 43%        -   b. Pheno AB=5,568 or 17%        -   c. Pheno B=13,173 or 39%            B. LDLC<130 mg/dL+HDLC>40 mg/dL=13,810    -   1. (B) with LDLIIIa+b 15%=70%    -   2. (B) with LDLIIIa+b 20%=43%    -   3. (B) with HDL 2b>20%=56%    -   4. (B) with LDLIIIa+b 15%+HDL 2b>20%=59%    -   5. (B) with LDLIIIa+b 20%+HDL 2b>20%=40%        C. LDLC<130 mg/dL+HDL2b<20%=13,168    -   1.(C) with LDLIIIa+b 15%=86%    -   2.(C) with LDLIIIa+b 20%=68%        D. LDLC<130 mg/dL+HDL2b>20%=3,642    -   1. (D) with LDLIIIa+b 15%=77%    -   2. (D) with LDLIIIa+b 20%=38%        E. LDLC<130 mg/dL+HDL2b>20%+Lp(a)>20 mg/dL=1,417    -   1. (E) with LDLIIIa+b 15%=77%    -   2. (E) with LDLIIIa+b 20%=38%        F. LDLC<130 mg/dL+Lp(a)>20 mg/dL=10,587    -   1. (F) with LDLIIIa+b 15%=73%    -   2. (F) with LDLIIIa+b 20%=52%        G. LDLC<130 mg/dL+HDLC>40 mg/dL=11,226    -   1. (G) with LDLIIIa+b 15%=70%    -   2. (G) with LDLIIIa+b 20%=43%        H. LDLC<130 mg/dL+TG<150 mg/dL=28,270    -   1. (H) with LDLIIIa+b 15%=70%    -   2. (H) with LDLIIIa+b 20%=42%    -   3. (H) with HDL 2b<20%=62%        I. LDLC<130 mg/dL+TG<180 mg/dL=24,796    -   1. (L) with LDLIIIa+b 15%=72%    -   2. (L) with LDLIIIa+b 20%=46%        J. LDLC<130 mg/dL+TG<180 mg/dL+HDL>40 mg/dL=16,723    -   1.(J) with LDLIIIa+b 15%=70%    -   2.(J) with LDLIIIa+b 20%=30%        K. LDLC<130 mg/dL+TG<180 mg/dL+HDL2b>20%=3,549    -   1. (K) with LDLIIIa+b 15%=68%    -   2. (K with LDLIIIa+b 20%=37%        Database Informatics (LDLC<100 mg/dL)-   (Total Database Volume: 65,536)-   (Total of patients with LDL IIIa+b values: 31,102 (47%))    A. LDLC<100 mg/dL=20,149 patients (44% of total volume)    -   1. LDLC<100 mg/dL with LDLIIIa+b 15%=85%    -   2. LDLC<100 mg/dL with LDLIIIa+b 20%=70%        -   a. Pheno A=8,411 or 42%        -   b. Pheno AB=3,431 or 17%        -   c. Pheno B=8,307 or 41%            B. LDLC<100 mg/dL+HDLC>40 mg/dL=11,334    -   1. (B) with LDLIIIa+b 15%=84%    -   2. (B) with LDLIIIa+b 20%=60%    -   3. (B) with HDL2b>20%=53%    -   4. (B) with LDLIIIa+b 15%+HDL 2b>20%=91%    -   5. (B) with LDLIIIa+b 20%+HDL 2b>20%=68%        C. LDLC<100 mg/dL+HDL2b>20%=2,772    -   1. (C) with LDLIIIa+b 15%=88%    -   2. (C) with LDLIIIa+b 20%=58%        D. LDLC<100 mg/dL+HDL2b<20%=5,906    -   1.(D) with LDLIIIa+b 15%=94%    -   2.(D) with LDLIIIa+b 20%=81%        E. LDLC<100 mg/dL+HDL2b>20%+Lp(a)>20 mg/dL=901    -   1.(E) with LDLIIIa+b 15%=92%    -   2.(E) with LDLIIIa+b 20%=63%        F. LDLC<100 mg/dL+Lp(a)>20 mg/dL=6,024    -   1.(F) with LDLIIIa+b. 15%=86%    -   2.(F) with LDLIIIa+b 20%=70%        G. LDLC<100 mg/dL+TG<180 mg/dL=14,414    -   1.(G) with LDLIIIa+b 15%=84%    -   2.(G) with LDLIIIa+b 20%=62%        H. LDLC<100 mg/dL+TG<150 mg/dL=12,513    -   1.(H) with LDLIIIa+b 15%=84%    -   2.(H) with LDLIIIa+b 20%=60%    -   3.(H) with HDL 2b<20%=61%        I. LDLC<100 mg/dL+TG<150 mg/dL+Lp(a)>20 mg/dL=4117    -   1.(I) with LDLIIIa+b 15%=85%    -   2.(I) with LDLIIIa+b 20%=61%

The above examples illustrate the present invention and are not intendedto limit it in spirit or scope.

1. A method for identifying patients with normal NCEP lipid levels whoare in need of treatment for cardiovascular disease comprising measuringone or more LDL or HDL particle subclass levels and identifying abnormalLDL or HDL subclass levels.
 2. The method of claim 1 wherein thesubclass is LDL III a+b.
 3. The method of claim 2 wherein the abnormallevel of LDLIII a+b is a level above 15% of the LDL particles.
 4. Themethod of claim 1 wherein the subclass is HDL 2b.
 5. The method of claim4 wherein the abnormal level of HDL 2b is a level below 20% of the HDLparticles.
 6. A method for identifying a human subject in need ofcardiovascular disease treatment comprising identifying subjects havingLDL III a+b levels of about 15% or more of the LDL particles.
 7. Themethod of claim 6 wherein HDL 2b is also measured.
 8. The methodaccording to claim 6 wherein the human subject has an LDLC<130 mg/dl. 9.The method according to claim 6 wherein the human subject has anLDLC<130 mg/dl.
 10. The method according to claim 6 wherein the humansubject has HDL 2b<20% of HDL particles.
 11. The method of claim 6wherein the LDL values are measured by gradient gel electrophoresis. 12.A method for identifying cardiovascular patients with LDL levels belowthe levels indicated by NCEP for initiation of therapeutic lifestylechanges or to initiate drug therapy comprising measure the portion ofsmall LDL particles to total LDL particles in the patient's blood serum.13. The method of claim 1 wherein the LDL and HDL subclass aredetermined by linear gel electrophoresis, gradient gel electrophoresis,ultracentrifuge, or ion mobility analysis.
 14. The method of claim 1wherein the LDL and HDL subclass are measured by gradient gelelectrophoresis.